Bay1002670, Fibroids, Safety and Efficacy EU,US,Can, Jap

Amenorrhea was defined as no scheduled or unscheduled bleeding/spotting after the end of the initial bleeding episode until end of treatment. Dose-response curve was estimated based on the primary endpoint. The 4 parameters characterizing the dose-response curve were reported in other pre-specified endpoints below.

In the below table, "N" signifies subjects who were evaluable for the specific parameter at that timepoint for each arm, respectively.

Onset of controlled bleeding was defined by the first day, for which the MBL (assessed by MP, Version 2014) for all subsequent 28-day periods up to the end of the treatment period was less than 80 mL. Kaplan-Meier estimated time to onset of controlled bleeding (days) was reported.

Pelvic Magnetic resonance imagings (MRI), without contrast agents, were performed for volume measurements of the uterus and fibroids preferably using 1.5 Tesla scanners or higher. Images were sent to the imaging core laboratory for evaluation. Volume measurements of the uterus and fibroids were performed centrally by independent radiologist(s).

Maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment. The nature of this exposure response analysis was the development of a model valid for the exposure response relationship over the entire range of available exposures (i.e. across all dose groups). Therefore, observations (exposure - induced amenorrhea) of all subjects need to be combined.

Area-under-the-curve (AUC) of vilaprisan between 0 and 24 hours post-dose at steady-state achieving 50% of maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with induced-amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment. The nature of this exposure response analysis was the development of a model valid for the exposure response relationship over the entire range of available exposures (i.e. across all dose groups). Therefore, observations (exposure - induced amenorrhea) of all subjects need to be combined.

The final exposure-response model was used to simulate the percentage of subjects below 90% of the maximum probability of induced amenorrhea (that is, all days with bleeding intensity 1 = none) for the selected doses 1, 2 and 3 mg (see table below).

The ability of the MP to identify subjects with HMB (defined as > 80 mL of blood loss during bleeding episode) per 28 days against the the current gold standard (i.e. AH method) was assessed. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MP method for detecting heavy menstrual bleeding were calculated against AH method. Sensitivity = true positive/(true positive + false negative)*100; Specificity = true negative/(true negative + false positive)*100; PPV = true positive/(true positive + false positive)*100; NPV = true negative/(true negative + false negative)*100. MP version 2014 was originally defined based on studies in healthy subjects. And MP version 2016 was developed for study population of women with heavy bleeding.

The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/δ]}. E0 is the amenorrhea rate for placebo; Emax is the maximum effect attributable to the drug (compared with the basal effect with dose at d=0 [placebo group], the maximum increase of drug effect).

The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/δ]}. ED50 is the dose at which 50% of Emax were achieved.

The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/δ]}. δ is hill slope parameter which measures sensitivity of the response to the dose range of the drug, determining the steepness of the dose-response curve.